Natural killer (NK) cells are a unique group of lymphocytes involved in surveillance and killing of foreign or infected cells through a mechanism involving recognition of HLA molecules by an extremely diverse set of receptors on the NK cell surface. The killer inhibitory receptor genes (KIRs) map to chromosome 19q13.4 along with other related genes. Some of these genes encode molecules that recognize HLA-C ligands, whereas others bind HLA-A and -B molecules. In contrast to cytotoxic T lymphocyte (CTL) recognition of peptide as presented by class I, NK cells destroy targets that lack expression of class I, and they are inhibited by recognition of class I on the cell surface. NK cells play an important role in defense against viruses that inhibit class I molecule expression and thereby avoid recognition by CTL. For example, HIV-1 downregulates cell surface expression of HLA-A and -B molecules (but not -C) and one mechanism to explain rapid progression to AIDS in individuals with certain HLA types may involve alteration of NK cell activity. The host defense system may be crippled effectively by reducing CTL activity through Nef downregulation of HLA-A and -B, along with curtailment of NK activity by not affecting the expression of HLA-C. Evidence for downregulation of class I by human papilloma virus (HPV) has also been reported. We have developed a molecular typing technique for the KIR genes in order to study potential effects of these genes on autoimmune (psoriatic arthritis [PsA], ankylosing spondylitis and multiple sclerosis) and infectious diseases (those associated with HIV-1, hepatitis C virus and hepatitis B virus). Haplotypes of the KIR gene complex vary in the number of KIR genes present and some of the genes are polymorphic. Our initial approach has been to determine presence or absence of each KIR gene, but we have also begun to develop means for typing alleles at each locus. It has become clear that defining the haplotypes will be necessary for rigorous disease association studies with this locus. Thus, we have begun typing 59 CEPH families for the KIR genes and preliminary data indicate extreme haplotypic complexity at the locus, presumably due to some combination of gene duplication, recombination, and intergenic rearrangements. Recognition of HLA-C molecules by several of the KIR gene products led us to speculate that synergistic interactions between HLA and KIR genes might be most obvious in data sets obtained from diseases associated with HLA-C. HLA associations with autoimmune diseases appear to be less complex than those involving infectious diseases. Thus, we have typed a group of over 300 individuals with psoriatic arthritis (PsA), a disease that has been shown to be associated with HLA-Cw*06 and this association is confirmed by our data. Further, the analysis indicates a strong association of PsA with the KIR gene 2DS1, which sends an activating signal to natural killer cells. Modelling the data to determine whether epistatic interactions between the unlinked HLA and KIR loci is in progress. Samples from individuals with another related autoimmune dissease, ankylosing spondylitis are also being typed. Finally, these genes are being typed in 265 individuals who have cleared HCV and 486 matched individuals who are persistently infected with HCV. This latter study should be of particular interest since NK cells are found in high frequency in the the liver and are known to induce apoptosis of hepatocytes in virally infected livers.